ON6 Targeted Therapies

Targeted cancer therapies are products of [blank_start]rational[blank_end] drug design, act on [blank_start]specific[blank_end] molecular targets, and are generally [blank_start]cytostatic[blank_end]. They interfere with specific molecules involved in cancer cell [blank_start]growth and survival[blank_end]. Can be: 1. [blank_start]Small molecule[blank_end] drugs, easily enter tumour cell or 2. [blank_start]Moncolonal antibodies[blank_end], bind to specific targets on cell surface

Tumour associated antigens (TIAs) are optimal blocking targets.

Products of activated oncogenes include cell surface receptors that [blank_start]activate[blank_end] tyrosine kinases. Tyrosine kinase [blank_start]autophosphorylates[blank_end] the receptors in the cell to make: [blank_start]vascular endothelium[blank_end] derived growth factor receptors, human [blank_start]epidermal[blank_end] growth factor, and [blank_start]platelet[blank_end]-derived growth factor receptors. These stimulate [blank_start]proliferation[blank_end] and block [blank_start]apoptosis[blank_end]. Chromosomal abnormalities are in cancer cells but not normal cells. [blank_start]Thee[blank_end] fusion gene which causes the abnormality makes fusion proteins that[blank_start]. drive[blank_end] cancer development. We can identify cancerous proteins and [blank_start]block[blank_end] their production. Example: Chronic [blank_start]myeloid leukaemia[blank_end] often have the Philadelphia chromosome, which creates a [blank_start]BCR-ABL[blank_end] fusion protein. In cancer it causes constitutively active [blank_start]tyrosine kinase[blank_end] activity.

Imatinib: First NIB approved by FDA. The suffix "nib" indicates a small-molecule [blank_start]inhibitor[blank_end] ("nib" is verbal shorthand for "inhibit") of kinase enzymes. - A small molecule [blank_start]intracellular[blank_end] inhibitor of tyrosine kinase - Treats chronic myeloid leukaemia; as it is selective for [blank_start]BCR-ABL[blank_end] TK fusion protein and competes with [blank_start]ATP[blank_end] for binding siten inhibiting phosphorylation (and [blank_start]proliferation[blank_end]). Other NIBs in clinical use: gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. - Share [blank_start]same[blank_end] mechanism of action (competitive ATP inhibition at catalytic binding site of TK) BUT difference is the [blank_start]spectrum[blank_end] of targeted kinases e.g. [blank_start]sunitinib[blank_end] inhibits signals from several Rs including VEGF and PDGRF families. NIBs are well tolerated but frequently cause [blank_start]myelosupression, rash, GI upset, fatigue[blank_end], arthralgia, & myalgia. Rarely cumulative cardiotoxicity: [blank_start]monitoring[blank_end] needed.

Targeted therapy with monoclonal antibodies: Target is angiogenesis, specifically the key targets [blank_start]VEGF-A and VEGFR2[blank_end]. Bevacizumab (brand name Avastin): [blank_start]recombinant humanized[blank_end] monoclonal v VEGF-A, given by [blank_start]intravenous[blank_end] infusion, first line for [blank_start]colorectal, lung, renal[blank_end] cancer. Mode of action: Prevents VEGF-A [blank_start]binding[blank_end] and so prevents tumour vascularisation and growth. Serious unwanted effects:, [blank_start]Hyper[blank_end]tension • Infections (from [blank_start]neutropaenia[blank_end]), impaired [blank_start]would[blank_end] healing, bleeding, GI perforation, haemorrhage. [blank_start]DVT, PE[blank_end] in the elderly.

Target: Human epidermal growth factor 2 (HER-2) Receptor coupled [blank_start]enzyme[blank_end], binds to EGF. • Normally promotes growth and [blank_start]differentiation[blank_end] • Integral [blank_start]tyrosine kinase[blank_end] activity inhibits p27 (cyclin dependent cell cycle [blank_start]regulator[blank_end]) • Stimulates [blank_start]proliferation[blank_end] • HER2 is found in 20-30% of breast tumours.

Trastuzumab (Herceptin): [blank_start]Humanised mouse[blank_end] monoclonal of HER2, for [blank_start]metastatic[blank_end] breast cancer. Mode of action: G1 [blank_start]arrest[blank_end] - less proliferation(no change in HER2 expression). Downregulates [blank_start]kinase[blank_end] activation, causing less [blank_start]PI3K, Akt[blank_end], which activates [blank_start]p27[blank_end] and halts cell cycle. Pertuzumab: inhibits HER2 [blank_start]dimerisation[blank_end].

Unwanted effects of monoclonal ABs: Mechanism dependent. Common: • [blank_start]Infusion[blank_end] related SEs ([blank_start]cytokine[blank_end] release syndrome), 1st infusion • [blank_start]Fever, chills,[blank_end] nausea and vomiting, hypersensitivity More Serious • [blank_start]Tumour Lysis Syndrome[blank_end] - release of cellular contents: high K+, P, uric acid, N, low Ca2+ = kidney [blank_start]failure[blank_end], seizures, [blank_start]cardiac[blank_end] arrhythmias, death. • Increased [blank_start]infection[blank_end] risk (HepB/reactivation) • Caution: autoimmune disease, HIV

Target: Cell surface glycoproteins. [blank_start]CD20[blank_end] antigen found on the surface of normal and malignant B lymphocytes, function unknown. Can activate [blank_start]B[blank_end] cells. Drug: Rituxumab. Mediates B cell [blank_start]lysis[blank_end]. - [blank_start]Complement[blank_end] dependent cytotoxicity (CDCC) - [blank_start]Antibody[blank_end] dependent cell-mediated cytotoxicity (ADCC) - Apotosis • [blank_start]Increases[blank_end] NK cell success from 40-80% Unwanted effects, most serious: • Cardiomyopathy • [blank_start]Infusion[blank_end] related SEs • Hypersensitivity ([blank_start]first[blank_end] infusion) • Myelosupression